Rate-controlled particles

ABSTRACT

Rate-controlled particles, comprising compounds of the formula 
     
       
         
         
             
             
         
       
     
     as a solid dispersion.

The present invention concerns pharmaceutical compositions in the form of rate-controlled particles, comprising compounds of the formula (I) to (VI)

(I) is an antiviral compound of formula

a N-oxide, a pharmaceutically acceptable addition salt or a stereochemically isomeric form thereof, wherein

-   Y is CR⁵ or N; -   A is CH, CR⁴ or N; -   n is 0, 1, 2, 3 or 4; -   Q is —NR¹R² or when Y is CR⁵ then Q may also be hydrogen; -   R¹ and R² are each independently selected from hydrogen, hydroxy,     C₁₋₁₂alkyl, C₁₋₁₂alkyloxy, C₁₋₁₂alkylcarbonyl,     C₁₋₁₂alkyloxycarbonyl, aryl, amino, mono- or di(C₁₋₁₂alkyl)-amino,     mono- or di(C₁₋₁₂alkyl)aminocarbonyl wherein each of the     aforementioned C₁₋₁₂alkyl groups may optionally and each     individually be substituted with one or two substituents each     independently selected from hydroxy, C₁₋₆alkyloxy,     hydroxy-C₁₋₆alkyloxy, carboxyl, C₁₋₆alkyloxycarbonyl, cyano, amino,     imino, aminocarbonyl, aminocarbonylamino, mono- or     di(C₁₋₆alkyl)amino, aryl and Het; or -   R¹ and R² taken together may form pyrrolidinyl, piperidinyl,     morpholinyl, azido or mono- or di(C₁₋₁₂alkyl)aminoC₁₋₄-alkylidene; -   R³ is hydrogen, aryl, C₁₋₆alkylcarbonyl, C₁₋₆alkyl,     C₁₋₆alkyloxy-carbonyl, C₁₋₆alkyl substituted with     C₁₋₆alkyloxycarbonyl; and -   each R⁴ independently is hydroxy, halo, C₁₋₆alkyl, C₁₋₆alkyloxy,     cyano, aminocarbonyl, nitro, amino, trihalomethyl,     trihalo-methyloxy, or when Y is CR⁵ then R⁴ may also represent     C₁₋₆alkyl substituted with cyano or aminocarbonyl; -   R⁵ is hydrogen or C₁₋₄alkyl; -   L is —X¹—R⁶ or —X²-Alk-R⁷ wherein     -   R⁶ and R⁷ each independently are phenyl or phenyl substituted         with one, two, three, four or five substituents each         independently selected from halo, hydroxy, C₁₋₆alkyl,         C₁₋₆alkyloxy, C₁₋₆alkylcarbonyl, C₁₋₆alkyloxycarbonyl, formyl,         cyano, nitro, amino, and trifluoromethyl; or when Y is CR⁵ then         R⁶ and R⁷ may also be selected from phenyl substituted with one,         two, three, four or five substituents each independently         selected from aminocarbonyl, trihalomethyloxy and trihalomethyl;         or when Y is N then R⁶ and R⁷ may also be selected from indanyl         or indolyl, each of said indanyl or indolyl may be substituted         with one, two, three, four or five substituents each         independently selected from halo, hydroxy, C₁₋₆alkyl,         C₁₋₆alkyloxy, C₁₋₆alkylcarbonyl, C₁₋₆alkyloxycarbonyl, formyl,         cyano, nitro, amino, and trifluoromethyl;     -   X¹ and X² are each independently —NR³—, —NH—NH—, —N═N—, —O—,         —S—, —S(═O)— or —S(═O)₂—;     -   Alk is C₁₋₄alkanediyl; or -   when Y is CR⁵ then L may also be selected from C₁₋₁₀alkyl,     C₃₋₁₀alkenyl, C₃₋₁₀alkynyl, C₃₋₇cycloalkyl, or C₁₋₁₀alkyl     substituted with one or two substituents independently selected from     C₃₋₇cycloalkyl, indanyl, indolyl and phenyl, wherein said phenyl,     indanyl and indolyl may be substituted with one, two, three, four or     where possible five substituents each independently selected from     halo, hydroxy, C₁₋₆alkyl, C₁₋₆alkyloxy, cyano, aminocarbonyl,     C₁₋₆alkyloxy-carbonyl, formyl, nitro, amino, trihalomethyl,     trihalomethyloxy and C₁₋₆alkylcarbonyl; -   aryl is phenyl or phenyl substituted with one, two, three, four or     five substituents each independently selected from halo, C₁₋₆alkyl,     C₁₋₆alkyloxy, cyano, nitro and trifluoromethyl; -   Het is an aliphatic or aromatic heterocyclic radical; said aliphatic     heterocyclic radical is selected from pyrrolidinyl, piperidinyl,     homopiperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl and     tetrahydrothienyl wherein each of said aliphatic heterocyclic     radical may optionally be substituted with an oxo group; and said     aromatic heterocyclic radical is selected from pyrrolyl, furanyl,     thienyl, pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl wherein     each of said aromatic heterocyclic radical may optionally be     substituted with hydroxy.

The compounds of formula (I) can be prepared according to the methods described in the patent applications with application number PCT/EP99/02043 and PCT/EP99/02044.

(II) is an antiviral compound of formula

the N-oxides, the pharmaceutically acceptable addition salts, quaternary amines and the stereochemically isomeric forms thereof, wherein

-   -b¹=b²-C(R^(2a))=b³-b⁴=represents a bivalent radical of formula

—CH═CH—C(R^(2a))═CH—CH═  (b-1);

—N═CH—C(R^(2a))═CH—CH═  (b-2);

—CH═N—C(R^(2a))═CH—CH═  (b-3);

—N═CH—C(R^(2a))═N—CH═  (b-4);

—N═CH—C(R^(2a))═CH—N═  (b-5);

—CH═N—C(R^(2a))═N—CH═  (b-6);

—N═N—C(R^(2a))═CH—CH═  (b-7);

-   q is 0, 1, 2; or where possible q is 3 or 4; -   R¹ is hydrogen, aryl, formyl, C₁₋₆alkylcarbonyl, C₁₋₆alkyl,     C₁₋₆alkyloxycarbonyl, C₁₋₆alkyl substituted with formyl,     C₁₋₆alkylcarbonyl, C₁₋₆alkyloxycarbonyl; -   R^(2a) is cyano, aminocarbonyl, mono- or di(methyl)aminocarbonyl,     C₁₋₆alkyl substituted with cyano, aminocarbonyl or mono- or     di(methyl)aminocarbonyl, C₂₋₆alkenyl substituted with cyano, or     C₂₋₆alkynyl substituted with cyano; -   each R² independently is hydroxy, halo, C₁₋₆alkyl optionally     substituted with cyano or —C(═O)R⁶, C₃₋₇cycloalkyl, C₂₋₆alkenyl     optionally substituted with one or more halogen atoms or cyano,     C₂₋₆alkynyl optionally substituted with one or more halogen atoms or     cyano, C₁₋₆alkyloxy, C₁₋₆alkyloxycarbonyl, carboxyl, cyano, nitro,     amino, mono- or di(C₁₋₆alkyl)amino, polyhalomethyl,     polyhalomethyloxy, polyhalomethylthio, —S(═O)_(p)R⁶,     —NH—S(═O)_(p)R⁶, —C(═O)R⁶, —NHC(═O)H, —C(═O)NHNH₂, —NHC(═O)R⁶,     —C(═NH)R⁶ or a radical of formula

wherein each A independently is N, CH or CR⁶;

-   -   B is NH, O, S or NR⁶;     -   p is 1 or 2; and     -   R⁶ is methyl, amino, mono- or dimethylamino or polyhalomethyl;

-   L is C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₃₋₇cycloalkyl, whereby     each of said aliphatic group may be substituted with one or two     substituents independently selected from     -   C₃₋₇cycloalkyl,     -   indolyl or isoindolyl, each optionally substituted with one,         two, three or four substituents each independently selected from         halo, C₁₋₆alkyl, hydroxy, C₁₋₆alkyloxy, cyano, aminocarbonyl,         nitro, amino, polyhalomethyl, polyhalomethyloxy and         C₁₋₆alkylcarbonyl,     -   phenyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl,         wherein each of said aromatic rings may optionally be         substituted with one, two, three, four or five substituents each         independently selected from the substituents defined in R²; or

-   L is —X—R³ wherein     -   R³ is phenyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl,         wherein each of said aromatic rings may optionally be         substituted with one, two, three, four or five substituents each         independently selected from the substituents defined in R²; and     -   X is —NR¹—, —NH—NH—, —N═N—, —O—, —C(═O)—, —CHOH—, —S—, —S(═O)—         or —S(═O)₂—;

-   Q represents hydrogen, C₁₋₆alkyl, halo, polyhaloC₁₋₆alkyl or —NR⁴R⁵;     and

-   R⁴ and R⁵ are each independently selected from hydrogen, hydroxy,     C₁₋₁₂alkyl, C₁₋₁₂alkyloxy, C₁₋₁₂alkylcarbonyl,     C₁₋₂₂alkyloxycarbonyl, aryl, amino, mono- or di(C₁₋₁₂alkyl)amino,     mono- or di(C₁₋₁₂alkyl)aminocarbonyl wherein each of the     aforementioned C₁₋₁₂alkyl groups may optionally and each     individually be substituted with one or two substituents each     independently selected from hydroxy, C₁₋₆alkyloxy,     hydroxyC₁₋₆alkyloxy, carboxyl, C₁₋₆alkyloxycarbonyl, cyano, amino,     imino, mono- or di(C₁₋₆alkyl)amino, polyhalomethyl,     polyhalomethyloxy, polyhalomethylthio, —S(═O)_(p)R⁶,     —NH—S(═O)_(p)R⁶, —C(═O)R⁶, —NHC(═O)H, —C(═O)NHNH₂, —NHC(═O)R⁶,     —C(═NH)R⁶, aryl and Het; or

-   R⁴ and R⁵ taken together may form pyrrolidinyl, piperidinyl,     morpholinyl, azido or mono- or di(C₁₋₁₂alkyl)aminoC₁₋₄alkylidene;

-   Y represents hydroxy, halo, C₃₋₇cycloalkyl, C₂₋₆alkenyl optionally     substituted with one or more halogen atoms, C₂₋₆alkynyl optionally     substituted with one or more halogen atoms, C₁₋₆alkyl substituted     with cyano or —C(═O)R⁶, C₁₋₆alkyloxy, C₁₋₆alkyloxycarbonyl,     carboxyl, cyano, nitro, amino, mono- or di(C₁₋₆alkyl)amino,     polyhalomethyl, polyhalomethyloxy, polyhalomethylthio, —S(═O)_(p)R⁶,     —NH—S(═O)_(p)R⁶, —C(═O)R⁶, —NHC(═O)H, —C(═O)NHNH₂, NHC(═O)R⁶,     —C(═NH)R⁶ or aryl;

-   aryl is phenyl or phenyl substituted with one, two, three, four or     five substituents each independently selected from halo, C₁₋₆alkyl,     C₃₋₇cycloalkyl, C₁₋₆alkyloxy, cyano, nitro, polyhaloC₁₋₆alkyl and     polyhaloC₁₋₆alkyloxy;

-   Het is an aliphatic or aromatic heterocyclic radical; said aliphatic     heterocyclic radical is selected from pyrrolidinyl, piperidinyl,     homopiperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl and     tetrahydrothienyl wherein each of said aliphatic heterocyclic     radical may optionally be substituted with an oxo group; and said     aromatic heterocyclic radical is selected from pyrrolyl, furanyl,     thienyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl wherein     each of said aromatic heterocyclic radical may optionally be     substituted with hydroxy.

The compounds of formula (II) can be prepared according to the methods described in the U.S. patent applications with application No. 60/143,962 and 60/107,792.

(III) is an antiviral compound of formula

a N-oxide, a pharmaceutically acceptable addition salt, a quaternary amine or a stereochemically isomeric form thereof, wherein -a¹=a²-a³=a⁴- represents a bivalent radical of formula

—CH═CH—CH═CH—  (a-1);

—N═CH—CH═CH—  (a-2);

—N═CH—N═CH—  (a-3);

—N═CH—CH═N—  (a-4);

—N═N—CH═CH—  (a-5);

-   n is 0, 1, 2, 3 or 4; and in case -a¹=a²-a³-a⁴- is (a-1), then n may     also be 5; -   R¹ is hydrogen, aryl, formyl, C₁₋₆alkylcarbonyl, C₁₋₆alkyl,     C₁₋₆alkyloxycarbonyl, C₁₋₆alkyl substituted with formyl,     C₁₋₆alkylcarbonyl, C₁₋₆alkyloxycarbonyl; and -   each R² independently is hydroxy, halo, C₁₋₆alkyl optionally     substituted with cyano or —C(═O)R⁴, C₃₋₇cycloalkyl, C₂₋₆alkenyl     optionally substituted with one or more halogen atoms or cyano,     C₂₋₆alkynyl optionally substituted with one or more halogen atoms or     cyano, C₁₋₆alkyloxy, C₁₋₆alkyloxycarbonyl, carboxyl, cyano, nitro,     amino, mono- or di(C₁₋₆alkyl)amino, polyhalomethyl,     polyhalomethyloxy, polyhalomethylthio, —S(═O)_(p)R⁴,     —NH—S(═O)_(p)R⁴, —C(═O)R⁴, —NHC(═O)H, —C(═O)NHNH₂, —NHC(═O)R⁴,     —C(═NH)R⁴ or a radical of formula

wherein each A independently is N, CH or CR⁴;

-   -   B is NH, O, S or NR⁴;     -   p is 1 or 2; and     -   R⁴ is methyl, amino, mono- or dimethylamino or polyhalomethyl;

-   L is C₄₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₃₋₇cycloalkyl, whereby     each of said aliphatic group may be substituted with one or two     substituents independently selected from     -   C₃₋₇cycloalkyl,     -   indolyl or isoindolyl, each optionally substituted with one,         two, three or four substituents each independently selected from         halo, C₁₋₆alkyl, hydroxy, C₁₋₆alkyloxy, cyano, aminocarbonyl,         nitro, amino, polyhalomethyl, polyhalomethyloxy and         C₁₋₆alkylcarbonyl,     -   phenyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl,         wherein each of said aromatic rings may optionally be         substituted with one, two, three, four or five substituents each         independently selected from the substituents defined in R²; or

-   L is —X—R³ wherein     -   R³ is phenyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl,         wherein each of said aromatic rings may optionally be         substituted with two, three, four or five substituents each         independently selected from the substituents defined in R²; and     -   X is —NR¹—, —NH—NH—, —N═N—, —O—, —C(═O)—, —CHOH—, —S—, —S(═O)—         or —S(═O)₂—; aryl is phenyl or phenyl substituted with one, two,         three, four or five substituents each independently selected         from halo, C₁₋₆alkyl, C₃₋₇cycloalkyl, C₁₋₆alkyloxy, cyano,         nitro, polyhaloC₁₋₆alkyl and polyhaloC₁₋₆alkyloxy.

The compounds of formula (III) can be prepared according to the methods described in the U.S. patent application with application No. 60/107,799.

(IV) is an antiviral compound of formula

the pharmaceutically acceptable acid addition salts and the stereochemically isomeric forms thereof, wherein

-   R¹ and R² are each independently selected from hydrogen; hydroxy;     amino; C₁₋₆alkyl; C₁₋₆alkyloxy; C₁₋₆alkylcarbonyl;     C₁₋₆alkyl-oxycarbonyl; Ar¹; mono- or di(C₁₋₆alkyl)amino; mono- or     di(C₁₋₆alkyl)aminocarbonyl; dihydro-2(3H)-furanone; C₁₋₆alkyl     substituted with one or two substituents each independently selected     from amino, imino, aminocarbonyl, aminocarbonyl-amino, hydroxy,     hydroxyC₁₋₆alkyloxy, carboxyl, mono- or di(C₁₋₆alkyl)amino,     C₁₋₆alkyloxycarbonyl and thienyl; or -   R¹ and R² taken together may form pyrrolidinyl, piperidinyl,     morpholinyl, azido or mono- or di(C₁₋₆alkyl)aminoC₁₋₄-alkylidene; -   R³ is hydrogen, Ar¹, C₁₋₆alkylcarbonyl, C₁₋₆alkyl,     C₁₋₆alkyloxycarbonyl, C₁₋₆alkyl substituted with     C₁₋₆alkyloxycarbonyl; and -   R⁴, R⁵, R⁶, R⁷ and R⁸ are each independently selected from hydrogen,     hydroxy, halo, C₁₋₆alkyl, C₁₋₆alkyloxy, cyano, aminocarbonyl, nitro,     amino, trihalomethyl or trihalomethyloxy -   L is C₁₋₁₀alkyl; C₃₋₁₀alkenyl; C₃₋₁₀alkynyl; C₃₋₇cycloalkyl; or -   L is C₁₋₁₀alkyl substituted with one or two substituents     independently selected from C₃₋₇cycloalkyl; indolyl or indolyl     substituted with one, two, three or four substituents each     independently selected from halo, C₁₋₆alkyl, C₁₋₆alkyloxy, cyano,     aminocarbonyl, nitro, amino, trihalomethyl, trihalomethyloxy,     C₁₋₆alkylcarbonyl; phenyl or phenyl substituted with one, two,     three, four or five substituents each independently selected from     halo, hydroxy, C₁₋₆alkyl, C₁₋₆alkyloxy, cyano, aminocarbonyl, nitro,     amino, trihalomethyl, trihalomethyloxy, C₁₋₆alkylcarbonyl; and,

Ar¹ is phenyl, or phenyl substituted with one, two or three substituents each independently selected from halo, C₁₋₆alkyl, C₁₋₆alkyloxy, cyano, nitro or trifluoromethyl; with the proviso that compounds (a) to (o)

Co. No. Alk R¹/R² R³ R⁴ R⁵ R⁶ R⁷ R⁸ a 1-(4-(2-methylpropyl)phenyl)ethyl H/H H CH₃ H H H H b 1-(4-(2-methylpropyl)phenyl)ethyl H/H H H H NO₂ H H c 1-(4-(2-methylpropyl)phenyl)ethyl H/H C₆H₅ H H H H H d 1-(4-(2-methylpropyl)phenyl)ethyl H/H H NO₂ H CH₃ H H e 1-(4-(2-methylpropyl)phenyl)ethyl H/H H H H NH₂ H H f 4-(2-methylpropyl)phenylmethyl H/H H H CF₃ H H H g 1-(4-(2-methylpropyl)phenyl)ethyl H/H H H H Cl H H h 4-(2-methylpropyl)phenylmethyl H/H H H H H H H i 3,4-dimethoxyphenylmethyl H/H H H H H H H j 2,3-dimethoxyphenylmethyl H/H H H H H H H k 3,4-diethoxyphenylmethyl H/H H H H H H H l 2-(3,5-(1,1-dimethylethyl)-4- H/H H H H H H H hydroxy-phenyl)ethyl m 2-(3,5-(1,1-dimethylethyl)-4- H/H H H t-Bu OH t-Bu H hydroxy-phenyl)ethyl n Phenylmethyl H/H H CH₃ H H H H o Phenylmethyl H/H H H H H H H are not included.

The compounds of formula (IV) can be prepared according to the methods described in EP-A-0834507.

(V) is an antifungal compound of formula

the N-oxide forms, the pharmaceutically acceptable acid addition salts and stereochemically isomeric forms thereof, wherein

-   n is zero, 1, 2 or 3; -   X is N or CH; -   each R¹ independently is halo, nitro, cyano, amino, hydroxy,     C₁₋₄alkyl, C₁₋₄alkyloxy or trifluoromethyl; -   R² is hydrogen; C₃₋₇alkenyl; C₃₋₇alkynyl, aryl; C₃₋₇cycloalkyl;     C₁₋₆alkyl or C₁₋₆alkyl substituted with hydroxy, C₁₋₄alkyloxy,     C₃₋₇cycloalkyl or aryl; -   R³ and R⁴ each independently are hydrogen, C₁₋₆alkyl, C₃₋₇cycloalkyl     or aryl; or -   R³ and R⁴ taken together form a bivalent radical —R³-R⁴— of formula:

-   -   wherein R^(5a), R^(5b), R^(5c), R^(5d) each independently are         hydrogen, C₁₋₆alkyl or aryl; and         aryl is phenyl or phenyl substituted with one, two or three         substituents selected from halo, nitro, cyano, amino, hydroxy,         C₁₋₄alkyl, C₁₋₄alkyloxy or trifluoromethyl.

The compounds of formula (V) can be prepared according to the methods described in WO 99/02523.

(VI) is an apolipoprotein-B synthesis inhibitor of formula

the N-oxides, the stereochemically isomeric forms thereof, and the pharmaceutically acceptable acid addition salts, wherein A and B taken together form a bivalent radical of formula

—N═CH—  (a),

—CH═N—  (b),

—CH₂—CH₂—  (c),

—CH═CH—  (d),

—C(═O)—CH₂—  (e),

—CH₂—C(═O)—  (f),

in the bivalent radicals of formula (a) and (b) the hydrogen atom may be replaced by C₁₋₆alkyl; in the bivalent radicals of formula (c), (d), (e), (f), one or two hydrogen atoms may be replaced by C₁₋₆alkyl;

-   R¹ is hydrogen, C₁₋₆alkyl or halo; -   R² is hydrogen or halo; -   R³ is hydrogen; C₁₋₈alkyl; C₃₋₆cycloalkyl; or C₁₋₈alkyl substituted     with hydroxy, oxo, C₃₋₆cycloalkyl or aryl; -   Het is a heterocycle selected from the group consisting of pyridine;     pyridine substituted with one or two substituents selected from     C₁₋₆alkyl, hydroxy, C₁₋₆alkyloxy, trihalomethyl, amino, mono- or     di(C₁₋₆alkyl)amino or aryl; pyrimidine; pyrimidine substituted with     one or two substituents selected from C₁₋₆alkyl, hydroxy,     C₁₋₆alkyloxy, trihalomethyl, amino, mono- or di(C₁₋₆alkyl)-amino or     aryl; tetrazole; tetrazole substituted with C₁₋₆alkyl or aryl;     triazole; triazole substituted with one or two substituents selected     from C₁₋₆alkyl, hydroxy, C₁₋₆alkyloxy, trihalomethyl, amino, mono-     or di(C₁₋₆alkyl)-amino; thiadiazole; thiadiazole substituted with     one or two substituents selected from C₁₋₆alkyl, hydroxy,     C₁₋₆alkyloxy, trihalomethyl, amino, mono- or di(C₁₋₆alkyl)-amino;     oxadiazole substituted with one or two substituents selected from     C₁₋₆alkyl, hydroxy, C₁₋₆alkyloxy, trihalomethyl, amino, mono- or     di(C₁₋₆alkyl)amino; imidazole; imidazole substituted with one or two     substituents selected from C₁₋₆alkyl, hydroxy, C₁₋₆alkyloxy,     trihalomethyl, amino, mono- or di(C₁₋₆alkyl)amino; thiazole;     thiazole substituted with one or two substituents selected from     C₁₋₆alkyl, hydroxy, C₁₋₆alkyloxy, trihalomethyl, amino, mono- or     di(C₁₋₆alkyl)amino; oxazole; oxazole substituted with one or two     substituents selected from C₁₋₆alkyl, hydroxy, C₁₋₆alkyloxy,     trihalomethyl, amino, mono- or di(C₁₋₆alkyl)amino; -   aryl is phenyl or phenyl substituted with C₁₋₆alkyl or halo.

The heterocyclic radical “Het” is bound to the sulfur atom via a carbon atom.

The compounds of formula (VI) can be prepared according to the methods described in WO 96/13499.

The particles comprise the compounds of formula (I) to (VI) as a solid dispersion in a polymeric matrix, wherein the polymeric matrix is consisting of a homo- or copolymer of N-vinyl-pyrrolidone. Furthermore, the invention concerns a process for manufacturing of such particles and pharmaceutical dosage forms comprising such particles.

The compounds of formula (I) to (VI) contained in the particles show poor bio-availability.

In order to improve the dissolution characteristics the compounds are dispersed in a polymeric matrix, preferably by using a melt-extrusion process.

EP-A 0 240 904 discloses a method for producing solid pharmaceutical forms by extrusion of polymer melts which contain active substances, using as polymers homo- or copolymers of N-vinyl-pyrrolidone.

EP-B 0 580 860 discloses a method for producing solid dispersions of drug substances in a polymeric matrix using a twin screw extruder.

It is an object of the present invention to provide rate-controlled pharmaceutical forms containing the aforementioned compounds.

We have found that this object is achieved by the particles defined at the outset.

Preferred compounds according to the invention are:

-   4-[[4-[(2,4,6-trimethylphenyl)amino]-2-pyrimidinyl]amino]benzo     nitrile; -   4-[[2-[(cyanophenyl)amino]-4-pyrimidinyl]amino]-3,5-dimethyl-benzonitrile; -   4-[[4-amino-5-chloro-6-[(2,4,6-trimethylphenyl)amino]-2-pyrimidinyl]-amino]benzonitrile; -   4-[[5-chloro-4-[(2,4,6-trimethylphenyl)amino]-2-pyrimidinyl]-amino]benzonitrile; -   4-[[5-bromo-4-(4-cyano-2,6-dimethylphenoxy)-2-pyrimidinyl]-amino]benzonitrile; -   4-[[4-amino-5-chloro-6-[(4-cyano-2,6-dimethylphenyl)amino]-2-pyrimidinyl]amino]benzonitrile; -   4-[[5-bromo-6-[(4-cyano-2,6-dimethylphenyl)amino]-2-pyrimidinyl]-amino]benzonitrile; -   4-[[4-amino-5-chloro-6-(4-cyano-2,6-dimethylphenyloxy)-2-pyrimidinyl]amino]benzonitrile; -   4-[[4-amino-5-bromo-6-(4-cyano-2,6-dimethylphenyloxy)-2-pyrimidinyl]amino]benzonitrile; -   4-[[4-[(2,4,6-trimethylphenyl)amino]-1,3,5-triazin-2-yl]amino]-benzonitrile; -   4-[[4-amino-6-[(2,6-dichlorophenyl)methyl]-1,3,5-triazin-2-yl]-amino]benzonitrile; -   4-[[4-[(2,6-dichlorophenyl)methyl]-6-(hydroxyamino)-1,3,5-triazin-2-yl]amino]benzonitrile; -   1-[4-[4-[4-[[4-(2,4-difluorophenyl)-4-(1H-1,2,4-triazol-1-yl-methyl)-1,3-dioxolan-2-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-3-(1-methylethyl)-2-imidazolidinone; -   (−)-[2S-[2alpha,4alpha(S*)]]-4-[4-[4-[4-[[2-(4-chlorophenyl)-2-[[(4-methyl-4H-1,2,4-triazol-3-yl)thio]methyl]-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-2,4-dihydro-2-(1-methyl-propyl)-3H-1,2,4-triazol-3-one,     a N-oxide, a pharmaceutically acceptable addition salt or a     stereochemically isomeric form thereof.

According to the present invention the term “rate-controlled” means that depending on the composition of the matrix the particles can show instant release of the active ingredient or modified release (sustained release).

The compounds according to the invention are homogeneously dispersed in a polymer matrix consisting of a homopolymer of N-vinylpyrrolidone or, preferably, a copolymer of N-vinyl-pyrrolidone. A preferred copolymer is a copolymer of N-vinyl-pyrrolidone and vinyl acetate, especially a copolymer obtained from 60% b.w. of NVP and 40% b.w. of vinylacetate.

The polymers show Fikentscher K values of from 17 to 90, preferably a K value of 30 (for the definition of the K value see “H. Fikentscher, Cellulose-Chemie” (1932), 58-64 and 71-74).

The polymeric matrix component is used in amounts of from 40 to 70, preferably of from 50 to 65% b.w. of the total weight of the particles.

In a preferred embodiment of the invention the polymeric matrix further comprises a surfactant, preferably a surfactant with a HLB-value of 10-18 (HLB: Hydrophilic Lipophilic Balance). Especially preferred surfactants are selected form the group consisting of low molecular weight polyoxyethylene polyoxy-propylene block copolymers with a mean molecular weight of 1000 to 6000 g/mol, and hydrogenated castor oil which can be modified with polyethylene glycol.

The amounts of surfactants used lies in the range of up to 20% b.w., preferably 5 to 15% b.w., of the particles.

In another preferred embodiment the matrix further comprises an organic carboxylic acid in amounts of up to 5% b.w. of the particles.

In another preferred embodiment of the invention the polymeric matrix further comprises hydroxypropyl methyl cellulose in amounts of up to 25% b.w., preferably from 5 to 10% b.w.

The particles of the present invention are prepared as solid dispersions of the active compounds in a polymeric matrix. The term “solid dispersion” is well known in the art and means a dispersion consisting of solid components. Preferably solid dispersions are in the form of solid solutions wherein the active ingredients are molecularly dispersed in the polymeric matrix.

Such solid dispersion is preferably obtained by forming a homogeneous mixture of the components in the form of a melt, extruding said melt and shaping of the extrudate. The melting is effected by the input of thermal and/or mechanic energy.

Depending on the composition of the matrix, the melting takes place in the range of from 40° C. to 190° C., preferably 50 to 150° C. The suitable temperature range depends on the glass transition temperature of the polymer component, the properties of the active ingredients and further additives. The optimal temperature range can be established by a few simple tests.

The mixing of the active substances with the polymer and additional components of the matrix can take place before or after the melting of the polymer. Preferably the process is solvent-free which means that no additional organic solvents or water are added.

The plastification and melting preferably can take place in an extruder, a kneader or a mixing reactor, preferably in an extruder having one or more screws which may rotate in the same direction or opposite directions, especially in a twin screw extruder. The latter can be operated with or without kneading elements, but use of kneading elements is preferred because mixing is better.

The still plastic material is extruded through a die or a breaker plate and then shaped into particles. This may be effected by milling and subsequent sieving the cooled extrudate. The preferred particle size for instant release forms lies in the range of from 0.5 to 1.5 mm.

The particles, optionally together with conventional pharmaceutically acceptable excipients, may be further processed to conventional pharmaceutical dosage forms such as tablets, pastilles, suppositories, or be packed in capsules.

It is possible and particularly advantageous to produce pharmaceutical forms with rate-controlled release and improved dissolution rates of the active ingredients. This was not to be expected in view of the low solubility of the active ingredients in aqueous media.

EXAMPLES General Method

Powder mixes of the components were melt kneaded at 145° C. for 5 min. After cooling the solidified melts were ground and sieved. The sieve fraction 0.5-1.5 mm was used for the dissolution tests.

The composition of the individual powder mixes is listed in Table 1.

TABLE 1 Example No. 1 2 3 4 5 6 Active ingredient¹⁾ 30 30 30 30 30 40 VP-VAC-copolymer²⁾ 65 55 55 60 55 47.1 Surfactant³⁾ 5 15 5 5 4.3 Citric acid 5 HPMC 10 8.6 Surfactant⁴⁾ 15 ¹⁾4-[[4-[2,4,6-trimethylphenyl)amino]-2-pyrimidinyl]amino]-benzonitrile ²⁾Kollidon ® VA64, VP/VAC = 60/40, BASF Aktiengesellschaft ³⁾PEG-n-hydrogenated Castoroil ⁴⁾polyoxyethylene polyoxypropylene blockcopolymer, mean mol. weight 4000 g/mol

The dissolution tests were carried out according to USP XXIII, paddle model, pH no change test, 0.1 M HCl, at 37° C., 100 rpm

The results are listed in Table 2.

TABLE 2 Dissolution Rates of particles according to examples 1-6 Dissolution [%] Dissolution [%] time Ex. 1 Ex. 2 Ex. 3 Ex. 4 time Ex. 5 Ex. 6 [min] (IR) (IR) (IR) (IR) [min] (SR) (SR) 5 53 65 58 57 1 10 73 86 88 82 2 15 77 91 95 89 3 20 81 91 96 93 4 30 87 94 99 94 6 60 92 93 96 94 8 96 95 120 93 94 97 95 IR: Instant Release SR: Sustained Release

DSC-Measurements were performed with the formulations according to examples 1 to 6 in open pans (air) at temperatures of from 20→250° C., with a heating rate of 10° C. per minute. There is no indication of crystalline drug substance in the solid dispersions. 

1. (canceled)
 2. Particles according to claim 16, wherein the copolymer of N-vinylpyrrolidone is a copolymer with vinyl acetate.
 3. Particles according to claim 16, further comprising a surfactant.
 4. Particles according to claim 3, wherein the surfactant is a PEG-n-hydrogenated castor oil.
 5. Particles according to claim 16, wherein the surfactant is a low molecular weight poly-oxyethylene polyoxypropylene block copolymer.
 6. Particles according to claim 16, further comprising citric acid in amounts of up to 5% b.w.
 7. Particles according to claim 16, wherein the home- or copolymer of N-vinylpyrrolidone is used in amounts of from 40 to 70% b.w. of the total weight of the dosage form.
 8. Particles according to claim 7, wherein the homo- or copolymer of N-vinylpyrrolidone is used in amounts of from 50 to 65% b.w.
 9. Particles according to claim 16, wherein the controlled release is an instant release of the drug.
 10. Particles according to a claim 16, wherein the controlled release is a sustained release.
 11. Particles according to claim 10, further comprising hydroxypropyl methyl cellulose in amounts of from 5 to 10% b.w.
 12. Particles according to claim 16, obtained by forming a homogeneous mixture of the components in the form of a melt, extruding said mixture and shaping of the extrudate.
 13. Particles according to claim 16, comprising a compound selected from the group consisting of 4-[[4-amino-5-chloro-6-[(2,4,6-trimethylphenyl)amino]-2-pyrimidinyl]-amino]benzonitrile; 4-[[5-chloro-4-[(2,4,6-trimethylphenyl)amino]-2-pyrimidinyl]amino]benzonitrile; 4-[[5-bromo-4-(4-cyano-2,6-dimethylphenoxy)-2-pyrimidin]amino]-benzonitrile; 4-[[4-amino-5-chloro-6-[(4-cyano-2,6-dimethylphenyl)amino]-2-pyrimidinyl]amino]benzonitrile; 4-[[5-bromo-6-[(4-cyano-2,6-dimethylphenyl)amino]-2-pyrimidinyl]-amino]benzonitrile; 4-[[4-amino-5-chloro-6-[(4-cyano-2,6-dimethylphenoxy)-2-pyrimidinyl]amino]benzonitrile; 4-[[4-amino-5-bromo-6-(4-cyano-2,6-dimethylphenyloxy)-2-pyrimidinyl]amino]benzonitrile; a N-oxide, a pharmaceutically acceptable addition salt or a stereochemically isomeric form thereof.
 14. Pharmaceutical dosage form, comprising particles according to claim
 16. 15. Pharmaceutical dosage forms according to claim 14, further comprising one or more pharmaceutically acceptable excipients
 16. Rate-controlled release particles, comprising a compound of formula II

an N-oxide, a pharmaceutically acceptable addition salt, a quaternary amine or a stereochemically isomeric form thereof, wherein -b¹=b²-C(R^(2a))=b³-b⁴=represents a bivalent radical of formula —CH═CH—C(R^(2a))═CH—CH═  (b-1); —N═CH—C(R^(2a))═CH—CH═  (b-2); —CH═N—C(R^(2a))═CH—CH═  (b-3); —N═CH—C(R^(2a))═N—CH═  (b-4); —N═CH—C(R^(2a))═CH—N═  (b-5); —CH═N-c(R^(2a))═N—CH═  (b-6); —N═N—C(R^(2a))═CH—CH═  (b-7); q is 0, 1, 2; or where possible q is 3 or 4; R¹ is hydrogen, aryl, formyl, C₁₋₆alkylcarbonyl, C₁₋₆alkyl, C₁₋₆alkyloxycarbonyl, C₁₋₆alkyl substituted with formyl, C₁₋₆alkylcarbonyl, C₁₋₆alkyloxycarbonyl; R^(2a) is cyano, aminocarbonyl, mono- or di(methyl)aminocarbonyl, C₁₋₆alkyl substituted with cyano, aminocarbonyl or mono- or di(methyl)aminocarbonyl, C₂₋₆alkenyl substituted with cyano, or C₂₋₆alkynyl substituted with cyano; each R² independently is hydroxy, halo, C₁₋₆alkyl optionally substituted with cyano or —C(═O)R⁶, C₃₋₇cycloalkyl, C₂₋₆alkenyl optionally substituted with one or more halogen atoms or cyano, C₂₋₆alkynyl optionally substituted with one or more halogen atoms or cyano, C₁₋₆alkyloxy, C₁₋₆alkyloxycarbonyl, carboxyl, cyano, nitro, amino, mono- or di(C₁₋₆alkyl)amino, polyhalomethyl, polyhalomethyloxy, polyhalomethylthio, —S(═O)R⁶, —NH—S(═O)_(p)R⁶, —C(═O)R⁶, —NHC(═O)H, —C(═O)NHNH₂, —NHC(═O)R⁶, —C(═NH)R⁶ or a radical of formula

wherein each A independently is N, CH or CR⁶; B is NH, O, S or NR⁶; p is 1 or 2; and R⁶ is methyl, amino, mono- or dimethylamino or polyhalomethyl; L is C₁₋₁₀alkyl, C₂₋₁₀alkenyl, C₂₋₁₀alkynyl, C₃₋₇cycloalkyl, whereby each of said aliphatic group may be substituted with one or two substituents independently selected from C₃₋₇cycloalkyl, indolyl or isoindolyl, each optionally substituted with one, two, three or four substituents each independently selected from halo, C₁₋₆alkyl, hydroxy, C₁₋₆alkyloxy, cyano, aminocarbonyl, nitro, amino, polyhalomethyl, polyhalomethyloxy and C₁₋₆alkylcarbonyl, phenyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl, wherein each of said aromatic rings may optionally be substituted with one, two, three, four or five substituents each independently selected from the substituents defined in R²; or L is —X—R³ wherein R³ is phenyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl, wherein each of said aromatic rings may optionally be substituted with one, two, three, four or five substituents each independently selected from the substituents defined in R²; and X is —NH—, —NH—NH—, —N═N—, —O—, —C(═O)—, —CHOH—, —S—, —S(═O)— or —S(═O)₂—; Q represents hydrogen, C₁₋₆alkyl, halo, polyhaloC₁₋₆alkyl or —NR⁴R⁵; and R⁴ and R⁵ are each independently selected from hydrogen, hydroxy, C₁₋₁₂alkyl, C₁₋₁₂alkyloxy, C₁₋₁₂alkylcarbonyl, C₁₋₂alkyloxycarbonyl, aryl, amino, mono- or di(C₁₋₁₂alkyl)amino, mono- or di(C₁₋₂alkyl)aminocarbonyl wherein each of the aforementioned C₁₋₂alkyl groups may optionally and each individually be substituted with one or two substituents each independently selected from hydroxy, C₁₋₆alkyloxy, hydroxyc₁₋₆alkyloxy, carboxyl, C₁₋₆alkyloxycarbonyl, cyano, amino, imino, mono- or di(C₁₋₆alkyl)amino, polyhalomethyl, polyhalomethyloxy, polyhalomethylthio, —S(O)_(p)R⁶, —NH—S(═O)_(p)R⁶, —C(═O)R⁶, —NHC(═O)H, —C(═O)NHNH₂, —NHC(O)R⁶, —C(═NH)R⁶, aryl and Het; or R⁴ and R⁵ taken together may form pyrrolidinyl, piperidinyl, morpholinyl, azido or mono- or di(C₁₋₂alkyl)aminoC₁₋₄-alkylidene; Y represents hydroxy, halo, C₃₋₇cycloalkyl, C₂₋₆alkenyl optionally substituted with one or more halogen atoms, C₂₋₆alkynyl optionally substituted with one or more halogen atoms, C₁₋₆alkyl substituted with cyano or —C(═O)R⁶, C₁₋₆alkyloxy, C₁₋₆alkyloxycarbonyl, carboxyl, cyano, nitro, amino, mono- or di(C₁₋₆alkyl)amino, polyhalomethyl, polyhalomethyloxy, polyhalomethylthio, —S(═O)_(p)R⁶, —NH—S(═O)_(p)R⁶, —C(═O)R⁶, —NHC(═O)H, —C(═O)NHNH₂, —NHC(═O)R⁶, —C(NH)R⁶ or aryl; aryl is phenyl or phenyl substituted with one, two, three, four or five substituents each independently selected from halo, C₁₋₆alkyl, C₃₋₇cycloalkyl, C₁₋₆alkyloxy, cyano, nitro, polyhaloC₁₋₆alkyl and polyhaloC₁₋₆alkyloxy; Het is an aliphatic or aromatic heterocyclic radical; said aliphatic heterocyclic radical is selected from pyrrolidinyl, piperidinyl, homopiperidinyl, piperazinyl, morpholinyl-, tetrahydrofuranyl and tetrahydrothienyl wherein each of said aliphatic heterocyclic radical may optionally be substituted with an oxo group; and said aromatic heterocyclic radical is selected from pyrrolyl, furanyl, thienyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl wherein each of said aromatic heterocyclic radical may optionally be substituted with hydroxy, as a solid dispersion in a polymeric matrix, wherein the polymeric matrix is consisting of a homo- or copolymer of N-vinylpyrrolidone. 